1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime derivatives, process for producing them and use thereof

ABSTRACT

The present invention relates to novel 1-acyl-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonic acid compound, processes for producing said compounds, intermediate compounds to produce said compounds and compositions containing said compounds with potent diuretic activity that can be used for treating and/or preventing hypertension, oedema and/or for removing ascites. 
     The present invention is based on the selection of 1-acyl-7-halo-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonic acid compounds, namely heterocyclic-or fused heterocyclic- carbonyl derivatives at 1 position. 
     The compounds of the present invention containing these substituents have potent hypotensive, antioedematous and diuretic effect as well as an activity to remove ascites and are extremely useful for the treatment of diseases and disorders mentioned above.

BACKGROUND OF THE INVENTION

The present invention relates to novel1-acyl-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acid compounds,process for producing said compounds, intermediate compounds, novel1-acyl-2,3-dihydro4(lH)-quinolinone compounds, to produce said compoundsand compositions containing said compounds with potent diuretic activitythat can be used for treating and/or preventing hypertension, oedemaand/or for removing ascites.

For the treatment of hypertension benzothiazide derivatives or so-calledloop diuretics have been widely used to lower blood pressure. Theseagents act mainly on the distal part of renal tubule or the loop ofHenle and increase renal excretion of electrolytes and water. Many ofthese diuretics, however, are known to show several adverse reaction incommon, for example, hypokalemia, hyperuricemia, decrease in sugartolerance and disorder in lipid metabolism.

Diuretic agents have also been used for the treatment of oedemaresulting from retention of water and electrolytes based on cardiac orrenal insufficiency or on metabolic disorders, but such conventionallyused diuretics show only marginal efficacy against retention of asciteswhich is often observed in the patients with abdominal tumor or livercirrhosis.

These benzothiazide diuretics and loop diuretics are known to sharecommon chemical substructures.

From the foregoing background, it has been desired to develop noveldiuretics that are useful in the treatment of hypertension, oedema andremoval of ascites and that do not cause aforementioned adversereactions by synthesizing compounds whose chemical structures are noveland different from those of known diuretics.

SUMMARY OF THE INVENTION

An object of the present invention is to provide novel1-acyl-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acid compoundsand salts thereof, solvates of said compounds and solvates of saidsalts.

Another object of the present invention is to provide processes forproducing novel 1-acyl-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonicacid compounds.

A further object of the present invention is to provide pharmaceuticalcompositions for treating hypertension, oedema and ascites whichcomprise novel 1-acyl-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonicacid compounds and salts thereof, solvates of said compounds andsolvates of said salts as active components.

A further object of the present invention is to provide intermediatecompounds, novel 1-acyl-2,3-dihydro-4(lH)-quinolinone compounds, in thesynthesis of 1-acyl-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonicacid compounds.

The present invention is based on the selection of1-acyl-7-halo-2,3-dihydro-4(lH)-qinolinone-4-oxime-O-sulfonic acidcompounds, namely heterocyclic- or fused heterocyclic-carbonylderivatives at 1 position.

The compounds of the present invention containing these substituentshave potent hypotensive, antioedematous and diuretic effect as well asan activity to remove ascites and are extremely useful for the treatmentof diseases and disorders mentioned above.

DETAILED DESCRIPTION OF THE INVENTION

As a result of extensive investigations concerning development of noveldihydroquinolinone oxime derivatives having a satisfactory diureticactivity, the present inventors have found that1-acyl-2,3-dihydro4(lH)-quinolinone-4-oxime-0-sulfonic acid compoundspossesses a potent diuretic activity that can be used for treatingand/or preventing hypertension, oedema and/or for removing ascites, thussatisfy these requirements and, have accomplished the present invention.

The present invention is directed to1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds represented by the formula (I): ##STR1## wherein R¹ representsa furyl group, an isoxazolyl group, a pyrrolyl group, a pyridazinylgroup, a pyrimidinyl group, a quinolyl group, a benzodioxolyl group, athienyl group, a pyridyl group, an indolyl group, an indenyl group or aphenyl group which may be substituted with at least one of an alkylgroup of straight or branched chain having 1 to 4 carbon atoms, analkylthio group, a halogen atom, an amino group, a protected aminogroup, a carboxyl group, an esterified carboxyl group or a phenyl group,X represents a halogen atom, and the bond shown with a wavy linerepresents a bond of anti-form or syn-form, and a salt thereof as wellas a solvate of said compound and a solvate of said salt.

With respect to pharmaceutical uses, the compounds posessing a chlorineatom at the 7-position of the formula (I), namely1-acyl-7-chloro-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acids,are particularly preferred.

The present invention is also directed to a process for preparingabove-mentioned1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds.

The present invention is further directed to pharmaceutical compositionsfor treating hypertension, oedema and removal of ascites characterizedby containing these1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds and salts thereof, solvates of said compounds and solvates ofsaid salts as active components.

The present invention is also directed to intermediate compounds, novel1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone compounds, in the synthesisof 1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds.

The compounds of the present invention represented by the formula (I) ischemically novel and can generally be produced according to the methodsdescribed below.

For example, known 7-chloro-2,3-dihydro-4(lH)-quinolinone (French Patent1,514,280) are reacted with reactive derivatives of carboxylic acids tobe introduced as the acyl moiety, preferably acid halides, in organicsolvents and, if necessary and desired, in the presence of deacidifyingagents to obtain 1-acyl-7-chloro-2,3-dihydro-4(lH)-quinolinone compoundsas intermediate compounds.

As the organic solvent, chloroform, dichloromethane, ether,tetrahydrofuran, dioxane, benzene or ethyl acetate may be used; as thedeacidifying agent, organic bases such as pyridine, triethylamine orN,N-dimethylaniline, or inorganic bases such as potassium carbonate,sodium carbonate or sodium bicarbonate may be used. As the acid halides,acid halides corresponding to R¹ in the formula (I), such as2-dimethylaminobenzoyl chloride, 3-methyl-2-thienylcarbonyl chloride,2-methyl-3-thienylcarbonyl chloride, 2-ethylthio-3-pyridylcarbonylchloride or 1-methyl-2-pyrrolylcarbonyl chloride may be used.

The intermediate compounds thus obtained,1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone compounds, are reacted withhydroxylamine in organic solvents such as methanol, ethanol,tetrahydrofuran or dimethylformamide to obtain corresponding1-acyl-7-halo-2.3-dihydro-4(lH)-quinolinone-4-oximes, which are thenreacted with sulfonating agents such as sulfur trioxide-pyridine complexor sulfur trioxide-dimethylformamide complex to obtain corresponding1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-0-sulfonic acidcompounds, and if necessary, said compounds may form salts thereof.

The above mentioned intermediate compounds,1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone compounds, may also bereacted with hydroxylamine-0-sulfonic acid in organic solvents such asmethanol, ethanol, tetrahydrofuran or dimethylformamide in the presenceof pyridine, N,N-dimethylaniline, potassium acetate, sodium carbonate orpotassium carbonate to obtain1-acyl-7-halo-2.3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds.

To demonstrate the utility of the compounds of the present invention,data on diuretic, antihypertensive and antioedematous activities as wellas the activity to remove ascites of representative compounds are shownbelow.

                                      TABLE 1                                     __________________________________________________________________________    Compound No.                                                                     1        2        3         4         5                                    __________________________________________________________________________    R.sup.1                                                                           ##STR2##                                                                               ##STR3##                                                                               ##STR4##                                                                                ##STR5##                                                                                ##STR6##                            __________________________________________________________________________    Compound No.                                                                     6        7        8         9         10                                   __________________________________________________________________________    R.sup.1                                                                           ##STR7##                                                                               ##STR8##                                                                               ##STR9##                                                                                ##STR10##                                                                               ##STR11##                           __________________________________________________________________________    Compound No.                                                                     11       12       13        14        15                                   __________________________________________________________________________    R.sup.1                                                                           ##STR12##                                                                              ##STR13##                                                                              ##STR14##                                                                               ##STR15##                                                                               ##STR16##                           __________________________________________________________________________

Experimental Example 1. Diuretic activity in dogs

Mongrel dogs weighing 7 to 15 kg were fasted overnight. The animals wererestrained in a supine position under pentobarbital anesthesia (30 mg/kgbody weight, i.v.), and physiological saline solution was continuouslyinfused into femoral vein via catheter at the rate of 0.15 ml/kg/min.The animals were then laparotomized and left urethra was cannulated tocollect urine in 10-minute periods. Compounds to be tested wereadministered intravenously and the changes in urine output was recorded.Percent increase in urine output was calculated by the formula givenbelow:

    ______________________________________                                        Increase in urine output                                                                      =     (Urine output in the 90                                                       minute period after the                                                       administration of the                                                         compound) - [(Urine out                                                       put in the 30-minute                                                          period before administra-                                                     tion) × 3]                                        Percent increase in                                                                           =     (Increase in urine output by                            urine output          the tested compound) + (In-                                                   crease in urine output by                                                     furosemide) × 100                                 ______________________________________                                    

The results are shown below:

                  TABLE 2                                                         ______________________________________                                                     Dose     Percent increase in                                     Compound     (μg/kg)                                                                             urine output                                            ______________________________________                                        Furosemide   100      100                                                     1            100      160                                                     3            100      191                                                     5            100      247                                                     7            100      217                                                     9            100      131                                                     13           100      221                                                     14           100      167                                                     15           100      176                                                     ______________________________________                                    

All of the tested compounds showed a significant diuretic activity.

Experimental Example 2. Suppressive effect on carrageenin-induced pawoedema in rats

Compound to be tested or phenylbutazone was orally administered togroups of Wistar rats (weighing ca. 120 g), each group consisting of 3to 5 animals. One hour after the administration, 0.1 ml of physiologicalsaline solution containing 1% of carrageenan was subcutaneously injectedto the left hind paw. The volume of each paw was measured before and 3hours after the injection of carrageenan, and the change in the volumewas divided by the volume before injection to calculate oedema index.The dose at which oedema is suppressed by 30%, ED₃₀, was calculated foreach compound. The results are shown below.

                  TABLE 3                                                         ______________________________________                                                        ED.sub.30                                                     Compound        (mg/kg)                                                       ______________________________________                                        Phenylbutazone  68                                                            4               15                                                            6               83                                                            8               32                                                            ______________________________________                                    

All of the tested compounds showed a significant antioedematous effect.

Experimental Example 3. Hypotensive action in spontaneously hypertensiverats

Compound to be tested was orally administered to groups of malespontaneously hypertensive rats (SHRs, weighing 250 to 300 g), eachgroup consisting of 3 to 5 animals, once a day for 7 consecutive days.Mean blood pressure of SHRs ranged from 170 to 190 mmHg. Blood pressurewas measured before and after the administration with a plethysmograph.The results are shown below.

                  TABLE 4                                                         ______________________________________                                                 Dose        Blood pressure                                           Compound   (mg/kg)       Before  After                                        ______________________________________                                        Control    --            184     182                                           5         10            183     161                                          11         10            183     164                                          12         10            180     167                                          ______________________________________                                    

Significant hypotensive activity was observed for all of testedcompounds.

Experimental Example 4. Removal of ascites from tumor-bearing mice

Two days after intraperitoneal transplantation of 10⁶ cells/animal ofP388 murine leukemia cells to 6-to 7-week old BDF₁ mice, compounds to betested were intravenously administered to groups of the tumorbearingmice, each group consisting of 6 animals. Five hours after theadministration, the volume of ascites was measured. The ratio of removalwas calculated for each compound on the relative volume of ascites. Theresults are shown below.

                  TABLE 5                                                         ______________________________________                                                      Dose     Ratio of removal                                       Compound      (mg/kg)  of ascites (%)                                         ______________________________________                                        Control       --        0                                                     Furosemide    100      19                                                     2             10       38                                                     4             10       24                                                     10            10       28                                                     ______________________________________                                    

All of the compounds tested showed significant activity, more potentthan furosemide, to remove ascites in tumor-bearing mice.

Experimental Example 5. Acute toxicity

Compounds to be tested were intraperitoneally administered to groups ofICR mice weighing about 20 g. Each group consisted of 5 animals. Sevendays after the administration, mortality was determined. The results areshown below.

                  TABLE 6                                                         ______________________________________                                                        Dose                                                          Compound        (mg/kg)  Mortality                                            ______________________________________                                         1              200      0/5                                                   5              200      0/5                                                   7              200      0/5                                                   8              200      0/5                                                  10              200      0/5                                                  13              200      0/5                                                  14              200      0/5                                                  15              200      0/5                                                  ______________________________________                                    

The doses of the experiment described above are considerably higher thanthat required for their pharmacological activity. Therefore, thesecompounds were deemed to have large margins for safety.

As demonstrated by the experimental examples described above, thesecompounds of the present invention possess a potent diuretic activitythat can be used for treating and/or preventing hypertension, oedemaand/or for removing ascites, and also a large margin for safety withinthe dose ranges to show these pharmacological activities. Therefore,these compounds are of great use in the treatment of oedema caused byfunctional insufficiency of heart, kidney or liver, hypertension andaccumulation of cancerous ascites.

The 1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds of the present invention represented by the formula (I) mayform pharmaceutically acceptable salts with organic or inorganic bases.Typical examples of suCh salts of the compounds represented by theformula (I) include pharmacologically acceptable salts such as alkalimetal salts such as sodium salts, potassium salts, etc.; alkaline earthmetal salts such as calcium salts, etc.; salts of organic bases such asammonium salts, benzylamine salts, diethylamine salts, etc.; salts ofamino acids such as arginine salts, lysine salts, etc.

The 1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds provided by the present invention can be employed aspharmaceutical compositions, for example, in the form of pharmaceuticalcompositions containing the1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompounds together with appropriate, pharmaceutically acceptablecarriers. The pharmaceutical composition may take a solid form, forexample, tablets, granules, subtilized granules, powders, capsules andsuppositories or a liquid form, for example, aqueous solutions forinjection or suspensions for injection prepared with suspendingexcipients such as Tween 80 or arabic gum. The compositions may beadministered orally or intravenously, but can also be administeredsubcutaneously, intradermally or intramuscularly. Further, thecomposition may be formulated for the administration by inhalation, forexample as aerosol, for topical application as ointment, or assuppositories. While dose varies depending upon age and conditions ofthe patient, conditions and kind of diseases, etc., from about 1 toabout 5000 mg, preferably from about 10 to about 1000 mg, can be used asa daily dose for an adult.

Hereafter the present invention will be described with reference to theexamples below but is not deemed to be limited thereof

Example 1 Preparation of7-chloro-2,3-dihydro-l-(2-dimethylaminobenzoyl)-4(lH)-quinolinone

To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (20 g), pyridine(26 g) and dioxane (200 ml) was added dropwise 2-dimethylaminobenzoylchloride (30 g) under cooling at 0° C. to 5° C. with stirring. Themixture was allowed to react at room temperature for additional 3 hours.The reaction mixture was poured into 500 ml of water, then shaken withadditional dichloromethane (1000 ml). The organic layer was washed oncewith 1 N HCl (100 ml), twice with water (200 ml each) then once withsaturated aqueous NaCl solution and dried over anhydrous sodium sulfate.Dichloromethane was removed in vacuo and the residue was recrystallizedwith dichloromethane and n-hexane to obtain7-chloro-2,3-dihydro-l-(2-dimethylaminobenzoyl)-4(lH)-quinolinone (yield35 g) as white crystal.

Melting point: 85.5-89.0° C.

IR (KBr, cm⁻¹): 1690, 1650, 1435, 1375

NMR (CDCl₃, ppm): 2.51 (6H, s), 2.78 (2H, t), 4.34 (2H, t), 6.88-7.93(7H, m).

Example 2

Preparation of7-chloro-2,3-dihydro-l-(2-dimethylaminobenzoyl)-4(lH)-quinolinone-4-oxime-O-sulfonicacid potassium salt.

To a mixture of7-chloro-2,3-dihydro-l-(2-dimethylaminobenzoyl)-4(lH)-quinolinone (14.5g), obtained in example 1, methanol (200 ml) and dichloromethane (200ml) was added 6.1 g of hydroxylamine-0-sulfonic acid with stirring atroom temperature. After stirring for 30 minutes at room temperature,aqueous solution of potassium carbonate (7.3 g in 10 ml of water) wasadded to the mixture at once and stirring was continued for another 2hours. Precipitated crystals were removed by filtration and the solventwas removed in vacuo. The residue was subjected to silica gel columnchromatography using a dichloromethane-methanol mixture (10 1), thenrecrystallized with a mixed solvent of methanol and carbon tetrachlorideto obtain7-chloro-2,3-dihydro1-(2-dimethylaminobenzoyl)-4(lH)-quinolinone-4-oximeO-sulfonic acid potassium salt (yield 10.0 g) as white crystal.

Melting point: 182° C. (decomposition)

IR (KBr, cm⁻¹): 1655, 1380, 1240.

NMR (DMSO-d₆, ppm): 2.44 (6H, s), 2.83 (2H, t), 4.24 (2H, t), 6.80-7.93(7H, m)

Example 3 Preparation of7-chloro-1-(2-ethylthio-3-pyridylcarbonyl)-2.3-dihydro-4(lH)-quinolinone.

To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (25 g), pyridine(32 g) and dioxane (200 ml) was added dropwise2-ethylthio-3-pyridylcarbonyl chloride (37 under cooling at 0 C. to 5°C. with stirring. The mixture was allowed to react at room temperaturefor additional 3 hours. The reaction mixture was subjected to theprocedure described in example 1, and 43 g of7-chloro-l-(2-ethylthio-3-pyridylcarbonyl)-2,3-dihydro-4(lH)-quinolinonewas obtained as white crystal.

Melting point: 120.0-122.8° C.

IR (KBr, cm⁻¹): 1700, 1640, 1400, 1370

NMR (CDCl₃, ppm): 1.16 (3H, t), 2.87 (2H, t), 3.13 (2H, q), 4.13 (2H,t), 7.12-8.57 (6H, m)

Example 4

Preparation of7-chloro-l-(2-ethylthio-3-pyridylcarbonyl)-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonicacid potassium salt (Compound 5)

To a mixture of7-chloro-1-(2-ethylthio-3-pyridylcarbonyl)-2,3-dihydro-4(lH)-quinolinone(10.0 obtained in example 3, methanol (150 ml) and dichloromethane (100ml) was added hydroxylamine-0-sulfonic acid (4 at room temperature withstirring. The mixture was stirred at room temperature for 30 minutes,and aqueous solution of potassium carbonate.(4.8 g in 20 ml of water)was added at once. The reaction mixture was stirred at room temperaturefor 2 hours, and the solvent was removed in vacuo. The residue wassubjected to silica gel column chromatography usingdichloromethanemethanol mixture (5 : 1) to obtain7-chloro-1-(2-ethylthio-3-pyridylcarbonyl)-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonicacid potassium salt (yield 10.0 g) as white crystal.

Melting point: l62.0° C. (decomposition)

IR (KBr, cm⁻¹): 1655, 1390, 1250

NMR (DMSO-d₆, ppm): 1.18 (3H, t), 2.90 (2H, t), 3.13 (2H, q), 3.80 (2H,t), 7.10-8.55 (6H, m).

Example 5 Preparation of7-chloro-2,3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone

To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (20.0 g),pyridine (26 g) and dichloromethane (200 ml) was added dropwise2-methyl-3-thienylcarbonyl chloride (26 g) at room temperature withstirring. The mixture was stirred under reflux for 4 hours. The reactionmixture was poured into 500 ml of water, then shaken with additionaldichloromethane (1000 ml). The organic layer was washed once with 1 NHCl (100 ml), twice with water (200 ml each) and once with saturatedaqueous NaCl solution, then dried over anhydrous sodium sulfate. Solventwas removed in vacuo and7-chloro-2,3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone(yield 28 g) was obtained as colorless oil.

IR (KBr, cm⁻¹): 1690, 1650, 1590, 1365

NMR (DMSO-d₆, ppm): 2.41 (3H, s), 2.84 (2H, t), 4.16 (2H, t), 7.01 (lH,d), 7.25-7.38 (3H, m), 7.88 (lH, d).

Example 6 Preparation of7-chloro-2.3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone-4-oxime-O-sulfonicacid potassium salt (compound 11). (Step 1)

To a mixture of7-chloro-2,3-dihydro-l-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone(17.5 g), obtained in example 5, and ethanol (250 ml) were addedhydroxyl amine hydrochloride (8 g) and pyridine (8.8 g), and the mixturewas heated under reflux for 1.5 hours. After cooling, the reactionmixture was poured into 1000 ml of water, and precipitated crystals wereseparated by filtration, washed, dried and recrystallized with ethanolto obtain7-chloro-2,3-dihydro-1-(2-methyl-3-thienylcarbonyl)-4(lH)-quinolinone-4-oxime(yield 16 g) as white crystal.

Melting point: 143.1° C. (decomposition)

IR (KBr, cm⁻¹): 3300, 1610, 1485, 1390

NMR (DMSO-d₆, ppm): 2.29 (3H, s), 2.85 (2H, t), 3.87 (2H, t), 6.92 (lH,d), 7.00 (lH, d), 7.18 (lH, dd), 7.32 (lH, d), 7.87 (lH, d), 11.55 (lH,s).

(Step 2)

The product of Step 1 (16 g) was dissolved in dichloromethane (250 ml)and sulfur trioxide-pyridine complex (8 g) was added. The reactionmixture was stirred at room temperature for 24 hours and the solvent wasremoved in vacuo. To the residue was added methanol (200 ml) and thenaqueous potassium carbonate solution (9 g in 10 ml of water) at once,and the mixture was subjected to the procedure described in example 4,and 13 g of 7-chloro-2,3-dihydro-1-(2-methyl-3-thienylcarbonyl)-4(lH)quinolinone-4-oxime-O-sulfonic acid potassium salt was obtained as whitecrystal.

Melting point: l67.7° C. (decomposition)

IR (KBr, cm⁻¹): 1660, 1390, 1280, 1250

NMR (DMSO-d⁶, ppm): 2.31 (3H, s), 2.85 (2H, t), 3.87 (2H, t), 6.93 (lH,d), 7.02 (lH, d), 7.23 (lH, dd), 7.32 (lH, d), 7.93 (lH, d).

Example 7 Preparation of7-chloro-2,3-dihydro-l-(l-methyl-2-pyrrolylcarbonyl)-4(lH)-quinolinone.

To a mixture of 7-chloro-2,3-dihydro-4(lH)-quinolinone (15 g), pyridine(12 g) and dichloromethane (200 ml) was added dropwise1-methyl-2-pyrrolyl chloride (17 g) under cooling at 0° C. to 5° C. withstirring. The mixture was subjected to the procedure described inexample 1, and 21 g of7-chloro-2,3-dihydro-1-(1-methyl-2-pyrrolylcarbonyl)-4(lH)-was obtainedas white crystal.

Melting point: 131.2-132.2° C.

IR (KBr, cm⁻¹): 1695, 1620, 1590, 1410, 1385

NMR (CDCl₃, ppm): 2.82 (2H, t), 3.90 (3H, s), 4.38 (2H, t), 6.06(lH,dd), 6.35 (lH,dd), 6.80 (lH, m), 7.12 (lH,dd), 7.28 (lH,dd), 7.96(lH, d).

Example 8 Preparation of7-chloro-2,3-dihydro-1-(1-methyl-2-pyrrolylcarbonyl)-4(lH)-quinolinone-4-oxime-O-sulfonicacid sodium salt.

To a mixture of7-chloro-2,3-dihydro-1-(1-methyl-2-pyrrolylcarbonyl)-4(lH)-quinolinone(14.5 g), obtained in example 7, methanol (200 ml) and dichloromethane(200 ml was added 6.8 of hydroxylamine-0-sulfonic acid with stirring atroom temperature After stirring for 30 minutes at room temperature,aqueous solution of sodium carbonate (6.4 g in 10 ml of water) was addedto the mixture at once and stirring was continued for another 2 hours.Precipitated crystals were removed by filtration and the solvent wasremoved in vacuo. The residue was subjected to silica gel columnchromatography using a dichloromethane-methanol mixture (10 1) to obtain7-chloro-2,3-dihydro-l-(l-methyl-2-pyrrolylcarbonyl)-4(lH)-quinolinone-4-oxime-O-sulfonicacid sodium salt (yield 12.0 g) as white crystal.

Melting point: 176.5° C. (decomposition)

IR (KBr, cm⁻¹): 1645, 1410, 1380, 1250

NMR (DMSO-d₆, ppm): 2.85 (2H, t), 3.78 (3H, s), 3.98 (2H, t), 6.00(lH,dd), 6.20 (lH,dd), 6.95 (lH, m), 7.06-7.24 (2H, m) 7.95 (lH, d).

Compounds of examples 9 to 69 are summarized to the following Tables 8to 9 together with corresponding IR and NMR data (NMR data weregenerally measured at 90 MHz except several data, which were measured at60 MHz and marked with asterisks(*), and NMR data were generallymeasured in DMSO-d⁶ except several data, which were measured in CDCl₃and marked with dagger ( )), and melting or decomposition points. Themethods by which these compounds are synthesized can be classified intothree groups as shown below.

                  TABLE 7                                                         ______________________________________                                                 Synthetic method (repre-                                                                       Example number                                      Group    sentative example number)                                                                      in Tables 8 to 9                                    ______________________________________                                        A        1, 3, 5, 7       40-69                                               B        2, 4              9-39                                               C        6                32-34                                               ______________________________________                                    

                                      TABLE 8                                     __________________________________________________________________________     ##STR17##                                                                    Exp.                                                                             Comp.                                Decomp.                               No.                                                                              No. R.sup.1      IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                          __________________________________________________________________________     9                                                                                    ##STR18##   1655, 1400, 1275, 1240                                                                2.92(2H, t), 3.92(2H, t), 7.20-7.36(2H, m),                                   7.80-8.15(3H, m), 9.30(1H, m)                                                             202.7                                 10                                                                                    ##STR19##   1675, 1580, 1420, 1280, 1250                                                          2.88(2H, t), 3.85(2H, t), 7.22-7.34(2H, m),                                   7.80-7.99(2H, m), 8.96-9.19(2H,                                                           209.5                                 11                                                                                    ##STR20##   1630, 1605, 1450, 1240                                                                2.45(3H, s),2.85(2H, t), 3.96(2H, t),                                         6.75(1H, d), 7.02-7.30(3H, m), 7.90(1H,                                                   165.5                                 12 8                                                                                  ##STR21##   1640, 1415, 1245                                                                      2.04(3H, s), 2.87(2H, t), 3.93(2H, t),                                        6.85-8.02 (5H, m)                                                                         103.0                                 13                                                                                    ##STR22##   1655, 1485 1280, 1235                                                                 2.11(3H, s), 2.84(2H, t), 3.86(2H, t),                                        7.11(1H, d), 7.17-7.29(2H, m), 7.68(1H, d),                                   7.94(1H, d) 171.3                                 14 10                                                                                 ##STR23##   1640, 1485 1420, 1245                                                                 2.86(2H, t), 3.89(2H, t), 7.12(1H, d),                                        7.20(1H, d) 7.26(1H, dd), 7.56(1H, d)                                         7.94(1H, d) 186.5                                 15                                                                                    ##STR24##   1640, 1410 1270, 1240                                                                 2.31(3H, s), 2.86(2H, t), 3.88(2H, t),                                        7.01(1H, d), 7.13(1H, d), 7.24(1H, dd)                                        7.62(1H, d), 7.94(1H, d)                                                                  183.2                                 16 7                                                                                  ##STR25##   1645, 1480, 1375, 1240                                                                1.14(3H, t), 2.75(2H, q), 2.84(2H, t),                                        3.86(2H, t), 6.93(1H, d), 7.12(1H, dd),                                       7.28(1H, d), 7.36(1H, d), 7.94(1H,                                                        163.4                                 17                                                                                    ##STR26##   1640, 1480, 1390, 1250                                                                2.84(2H, t), 3.95(2H, t), 6.60(1H, dd),                                       6.95-7.10 (2H, m), 7.22(1H, dd), 7.78(1H, d),                                 7.92(1H, d) 146.4                                 18 12                                                                                 ##STR27##   1640, 1610, 1480, 1390, 1250                                                          2.84(2H, t), 3.92(2H, t), 6.46(1H, d),                                        7.15-7.35 (2H, m), 7.68(1H, m), 7.92(1H, d),                                  8.04(1H, s) 155.9                                 19 1                                                                                  ##STR28##   1645, 1410, 1380, 1250                                                                2.82(2H, t), 3.78(3H, s), 3.96(2H, t),                                        6.00(1H, dd) 6.20(1H, dd), 6.95(1H, m),                                       7.06-7.24(2H, m), 7.95(1H, d)                                                             172.8                                 20                                                                                    ##STR29##   1650, 1410, 1380, 1245                                                                2.88(2H, t), 3.84(2H, t), 7.18-7.34(2H, m),                                   7.98(1H, d), 8.20(1H, s), 8.60(1H, d),                                        8.80(1H, d) 167.6                                 21 3                                                                                  ##STR30##   1660, 1480, 1380, 1280, 1240                                                          2.50(3H, s), 2.84(2H, t), 3.76(2H, t),                                        7.15-7.65(3H, m), 7.84-8.05(2H, m), 8.56(1H,                                  dd)         210.8                                 22 4                                                                                  ##STR31##   1660, 1390, 1240                                                                      2.48(3H, s), 2.89(2H, t), 3.79(2H, t),                                        7.10-8.57(6H, m)*                                                                         191.0                                 23                                                                                    ##STR32##   1660, 1390, 1240                                                                      0.84(3H, t), 1.36(6H, m), 2.89(2H, t),                                        3.13(2H, t), 3.81(2H, t), 7.21-8.54(6H,                                                   162.0                                 24 13                                                                                 ##STR33##   1660, 1420, 1245                                                                      2.10(3H, s), 2.24(3H, s), 2.88(2H, t),                                        3.91(2H, t), 7.21-8.05(3H, m)*                                                            169.0                                 25                                                                                    ##STR34##   1645, 1380, 1260, 1240                                                                1.96(3H, s), 2.88(2H, t), 3.70(2H, s),                                        3.93(2H, t), 7.20(1H, d), 7.20-7.55(5H, m)                                    7.96(1H, d) 203.8                                 26                                                                                    ##STR35##   1655, 1400 1380, 1245                                                                 2.92(2H, t), 3.65(2H, t), 7.33(1H, d),                                        7.70-8.16(7H, m), 8.99(1H, d)                                                             222.8                                 27                                                                                    ##STR36##   1640, 1480, 1400, 1240                                                                2.89(2H, t), 3.86(3H, s), 4.02(2H, t),                                        6.65(1H, s), 7.08-7.62(6H, m), 7.97(1H,                                                   176.6                                 28 14                                                                                 ##STR37##   1654, 1648, 1613, 1558, 1484, 1406, 1276,                                             1.81(3H, s), 2.09(3H, s), 2.85(2H, t),                                        3.90(2H, t), 7.06(1H, d), 7.26(1H, dd),                                       7.35(1H, s), 7.94(1H, d)                                                                  152.9                                 29 15                                                                                 ##STR38##   1654, 1457, 1380, 1244, 1066                                                          2.82(2H, t), 3.89(2H, t), 5.84(2H, s),                                        6.94-7.37(5H, m), 7.96(1H, d)                                                             117.4                                 30                                                                                    ##STR39##   1656, 1393, 1270, 1235, 1068                                                          2.25(3H, s), 2.87(2H, t), 3.30(2H, t),                                        7.08-7.38(3H, m), 7.97(1H, d), 8.34-8.58(2H,                                  m)          222.8                                 31                                                                                    ##STR40##   1655, 1396, 1273, 1245, 1067                                                          0.86(3H, t), 1.20-1.70(4H, m), 2.60(2H, t),                                   2.84(2H, t), 3.78(2H, t), 7.20-7.40(3H, m),                                   7.97(1H, d), 8.40-8.60(2H, m)                                                             178.0                                 32                                                                                    ##STR41##   1652, 1590, 1536, 1400, 1258                                                          2.77(2H, t), 3.62(3H, s), 3.95(2H, t),                                        6.04(1H, dd), 6.70(1H, t), 7.13-7.24(3H, m),                                  7.91(1H, d) 165.2                                 33                                                                                    ##STR42##   1661, 1395, 1272, 1247, 1120, 1067                                                    1.20(6H, d), 2.85(2H, t), 3.05(1H, m),                                        3.75(2H, t), 7.25-7.36(3H, m), 7.76-8.02(2H,                                  m), 8.62(1H, dd)                                                                          198.8                                 34                                                                                    ##STR43##   1655, 1630, 1410, 1239, 1064                                                          1.22(3H, t), 2.89(2H, t), 3.06(2H, q),                                        3.81(2H, t), 7.21(1H, s), 7.23(1H, d),                                        7.41(1H, d), 7.96(1H, d), 8.46(1H, d),                                        8.46(1H, s) 171.2                                 35 2                                                                                  ##STR44##   1665, 1395, 1215                                                                      2.93(2H, t), 3.90(2H, t), 7.20-7.62(3H, m),                                   7.95-8.06(2H, m), 8.70-8.77(2H,                                                           208.9                                 36 6                                                                                  ##STR45##   1640, 1405, 1225                                                                      2.91(2H, t), 3.80(2H, t), 7.24-7.53(2H, m),                                   7.90-8.09(3H, m), 8.88-8.98(2H,                                                           242.0                                 37 9                                                                                  ##STR46##   1640, 1405, 1240                                                                      2.87(2H, t), 3.93(2H, t), 7.09-8.02(6H,                                                   155.8                                 38                                                                                    ##STR47##   1725, 1665, 1390, 1240                                                                2.84(2H, t), 3.74(5H, m), 7.17-8.02(7H,                                                   156                                   39                                                                                    ##STR48##   1650, 1380, 1240                                                                      2.8(2H, t), 4.0(2H, t), 7.0-7.7(12H,                                                      150.5                                 __________________________________________________________________________     NMR data marked with asterisks(*) were measured at 60 MHz.               

                                      TABLE 9                                     __________________________________________________________________________     ##STR49##                                                                    Exp.                                M. P.                                     No.                                                                              R.sup.1      IR(KBr, cm.sup.-1)                                                                    NMR(DMSO-d.sub.6, ppm)                                                                    (°C.)                              __________________________________________________________________________    40                                                                                ##STR50##   1695, 1660, 1590, 1380                                                                2.88(2H, t), 4.22(2H, t), 7.28-7.55(2H, m),                                   7.80-8.20(3H, m), 9.30(1H, m)                                                             174.7˜176.3                         41                                                                                ##STR51##   1690, 1655, 1590, 1370                                                                2.86(2H, t), 4.18(2H, t), 7.32-7.67(2H, m),                                   7.85-7.99(2H, m), 9.04-9.26(2H,                                                           148.2˜151.3                         42                                                                                ##STR52##   1690, 1630, 1595, 1460, 1365                                                          2.52(3H, s), 2.82(2H, t), 4.34(2H, t), 6.65(1H,                               d), 7.05-7.30(3H, m), 7.92(1H, d)                                                         131.2˜133.4                         43                                                                                ##STR53##   1695, 1640, 1470, 1420, 1360                                                          2.11(3H, s), 2.85(2H, t), 4.22(2H,                                            t), 6.90-7.96(5H, m)*                                                                     93.0˜99.5                           44                                                                                ##STR54##   1690, 1650, 1590, 1440                                                                2.23(3H, s), 2.82(2H, t), 4.28(2H,                                            t), 6.98-7.03(1H, m) 7.15(1H, d), 7.16(1H, dd)                                7.40(1H, d), 7.98(1H, d)                                                                  oil                                       45                                                                                ##STR55##   1690, 1645, 1590, 1460                                                                2.85(2H, t), 4.20(2H, t), 7.22(1H, d), 7.28(1H,                               d), 7.33(1H, dd), 7.58(1H, d) 7.88(1H,                                                    109.1˜110.8                         46                                                                                ##STR56##   1690, 1650, 1595, 1400                                                                2.36(3H, s), 2.83(2H, t), 4.19(2H,                                            t), 7.15-7.20(2H, m), 7.30(1H, dd), 7.64(1H, d),                              7.87(1H, d) oil                                       47                                                                                ##STR57##   1690, 1660, 1585, 1460                                                                1.28(3H, t), 2.84(2H, q), 2.95(2H, t), 4.27(2H,                               t), 6.83(1H, d), 7.07-7.21(3H, m), 7.95(1H, d)                                            oil                                       48                                                                                ##STR58##   1690, 1640, 1580, 1560, 1470                                                          2.82(2H, t), 4.30(2H, t), 6.50(1H,                                            dd), 7.02-7.28(3H, m), 7.42(1H, d), 7.90(1H, d)                                           132.0˜134.2                         49                                                                                ##STR59##   1695, 1650, 1595, 1480, 1400                                                          2.82(2H, t), 4.30(2H, t), 6.30(1H,                                            d), 7.10-7.45(3H, m), 7.80(1H, s), 7.95(1H, d)                                            151.3˜152.7                         50                                                                                ##STR60##   1680, 1655, 1590, 1365                                                                2.88(2H, t), 4.30(2H, t), 7.15(1H, d), 7.25(1H,                               dd) 7.95-8.10(2H, m), 8.60(1H, d), 8.82(1H, d)                                            166.5˜168.9                         51                                                                                ##STR61##   1685, 1635, 1580, 1465, 1365                                                          2.46(3H, s), 2.80(2H, t), 4.02(2H, t), 7.15-7.40                              (2H, m), 7.55(1H, m), 7.75-7.94(2H, m), 8.50(1H,                              dd)         102.5˜106.4                         52                                                                                ##STR62##   1700, 1650, 1560, 1400, 1360                                                          2.49(3H, s), 2.85(2H, t), 4.10(2H,                                            t), 7.12-8.58(6H, m)*                                                                     170.0˜171.0                         53                                                                                ##STR63##   1700, 1655, 1400, 1370                                                                0.84(3H, t), 1.33(6H, m), 2.87(2H, t), 3.11(2H,                               t), 4.14(2H, t), 7.11-8.56(6H, m)*                                                        90.5˜92.0                           54                                                                                ##STR64##   1700, 1655, 1420, 1370                                                                2.15(3H, s), 2.31(3H, s), 2.85(2H, t), 4.20(2H,                               t), 7.25-7.98(3H, m)*                                                                     146.0˜148.0                         55                                                                                ##STR65##   1685, 1640, 1590, 1370                                                                2.04(3H, s), 2.87(2H, t), 3.75(2H, s), 4.22(2H,                               t), 7.20-7.60(6H, m), 7.90(1H, d)                                                         114.0˜118.7                         56                                                                                ##STR66##   1695, 1645, 1590, 1370                                                                2.82(2H, t), 3.95(2H, t), 7.41(1H,                                            dd), 7.67-8.18(7H, m), 9.02(1H,                                                           167.9˜170.2                         57                                                                                ##STR67##   1695, 1645, 1590, 1465                                                                2.88(2H, t), 3.89(3H, s), 4.27(2H, t), 6.81(1H,                               s), 7.02-7.65(6H, m), 7.91(1H, d)                                                         73.1˜77.5                           58                                                                                ##STR68##   1697, 1654, 1595, 1401                                                                1.87(3H, d), 2.21(3H, s), 2.80(2H, t), 4.29(2H,                               t), 7.08-7.26(3H, m), 7.95(1H, d)                                                         oil                                       59                                                                                ##STR69##   1687, 1651, 1597, 1565, 1472, 1458, 1368,                                             2.84(2H, t), 4.30(2H, t), 5.70(2H,                                            s), 6.90-7.26(5H, m), 7.95(1H, d)                                                         195.5˜196.5                         60                                                                                ##STR70##   1697, 1655, 1594, 1375                                                                2.38(3H, s), 2.82(2H, t), 4.20(2H,                                            t), 7.05-7.32(3H, m), 7.98(1H, d), 8.28-8.58(2H,                              m)          oil                                       61                                                                                ##STR71##   1698, 1662,  1593, 1374                                                               0.93(3H, t), 1.20-1.90(4H, m), 2.50-3.00(4H, m),                              4.17(2H, t), 7.20-7.60(3H, m), 7.99(1H, d),                                   8.51(1H, d), 8.60(1H, s)                                                                  oil                                       62                                                                                ##STR72##   1689, 1634, 1595, 1208                                                                2.79(2H, t), 3.67(3H, s), 4.32(2H, t), 6.10(1H,                               dd), 6.50(1H, t), 7.03-7.15(2H, m), 7.34(1H, d),                              7.92()1H, d)                                                                              128.4˜131.5                         63                                                                                ##STR73##   1696, 1654, 1593, 1381                                                                1.27(6H, d), 2.79(2H, t), 3.14(1H, m), 4.14(2H,                               t), 7.11-7.27(2H, m), 7.47-7.58(2H, m), 7.99(1H,                              d), 8.69(1H, dd)                                                                          150.6˜153.2                         64                                                                                ##STR74##   1697, 1654, 1595, 1570, 1467, 1375, 1208                                              1.20(3H, t), 2.87(2H, t), 3.07(2H, q), 4.12(2H,                               t), 7.33(1H, d), 7.34(1H, s), 7.40(1H, d),                                    7.88(1H, d), 8.47(1H, d), 8.51(1H,                                                        oil                                       65                                                                                ##STR75##   1690, 1635, 1470, 1360                                                                [DMSO-d.sub.6 /CDCl.sub.3 ] 2.90(2H, t), 4.21(2H,                             t), 7.26-7.58(3H, m), 7.90-8.09(2H,                                           m), 8.70-8.86(2H, m)                                                                      175.8˜177.8                         66                                                                                ##STR76##   1685, 1640, 1490, 1400                                                                2.93(2H, t), 4.10(2H, t), 7.35-8.01(2H, m),                                   8.07-8.25(2H, m) 8.60-8.82(1H, m), 8.94-9.02(2H,                              m)          171.7˜179.2                         67                                                                                ##STR77##   1660, 1640, 1475, 1345                                                                2.86(2H, t), 4.32(2H, t), 7.11-8.02(6H,                                                   165.1˜166.9                         68                                                                                ##STR78##   1725, 1700, 1675, 1375                                                                2.81(2H, t), 4.01(5H, m), 7.22-7.96(7H,                                                     129˜130.5                         69                                                                                ##STR79##   1695, 1650, 1365                                                                      2.1(2H, t), 3.4(2H, t), 6.8-7.8(12H,                                                      129.5˜131.5                         __________________________________________________________________________     NMR data marked with asterisks (*) were measured at 60 MHz.                   NMR data marked with dagger () were measured in CDCl.sub.3.              

Now, typical but non-limiting examples of formulations of the compoundof this invention will be shown below.

Formulation 1 (Capsules)

Compound 13, 40 g of weight, 645 g of lactose and 15 g of magnesiumstearate were weighed and mixed until the mixture became homogeneous Themixture was then filled in No. 1 hard gelatin capsule at 350 mg each toobtain capsule preparation.

Formulation 2 (Tablets)

Compound 7, 50 g of weight, 800 g of lactose. 120 g of potato starch, 15g of polyvinyl alcohol and 15 g of magnesium stearate were weighed. Theweighed amount of compound 7, lactose and potato starch were mixed untilaccomplishing homogeneity. Then aqueous solution of polyvinylalcohol wasadded to the mixture and granulated by wet process. The granules werethen dried, mixed with magnesium stearate and pressed into tablets, eachweighing 200 mg.

Formulation 3 (Powder)

Compound 15, 100 g of weight, 890 g of lactose and 10 g of magnesiumstearate were weighted and mixed until the mixture became homogeneous toobtain 10% powder preparation.

Formulation 4 (Rectal suppository)

Compound 3, 100 g of weight, 180 g of polyethyleneglycol 1500, 720 ofpolyethyleneglycol 4000 were ground well in a mortar and formulated intosuppository by melting and casting in appropriate mold.

Formulation 5 (Injection)

Compound 5, 1 of weight, was weighed and dissolved in 200 ml ofdistilled water for injection. The solution was filtered, sterilized.Two milliliters each of the sterilized solution was poured into 5-mlampoules and sealed to obtain preparation for injection.

What is claimed is:
 1. A1-acyl-7-halo-2,3-dihydro-4(1H)-quinolinone-4-oxime-O-sulfonic acidcompound represented by the formula (I): ##STR80## wherein R¹ representsa phenyl group substituted with at least one of an alkylthio group, anamino group which may be substituted with one or two alkyl groups ofstraight or branched chain having 1 to 4 carbon atoms, a carboxyl group,an alkyloxycarbonyl group of straight or branched chain having 1 to 4carbon atoms or a phenyl group, or wherein R¹ represents a furyl group,an isoxazolyl group, a pyrrolyl group, a pyridazinyl group, apyrimidinyl group, a quinolyl group, a benzodioxolyl group, a thienylgroup, a pyridyl group, an indolyl group or an indenyl group any one ofwhich may be substituted with at least one of an alkyl group of straightor branched chain having 1 to 4 carbon atoms, an alkylthio group, ahalogen atom, an amino group which may be substituted with one or twoalkyl groups of straight or branched chain having 1 to 4 carbon atoms, acarboxyl group, an alkyloxycarbonyl group of straight or branched chainhaving 1 to 4 carbon atoms or a phenyl group, provided that when R¹represents a thienyl group or a pyridyl group, either group issubstituted with at least one of said substituents, X represents ahalogen atom, and the bond shown with a wavy line represents a bond ofanti-form or syn-form, and a salt thereof as well as a solvate of saidcompound and a solvate of said salt.
 2. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents aN-methylpyrrol-2-yl group.
 3. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents furyl group.
 4. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a2,4-dimethylfuran-3-yl group.
 5. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a2-methylthiophen-3-yl group.
 6. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a3-methylthiophen-2-yl group.
 7. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a4-methylthiophen-3-yl group.
 8. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a2-ethylthiophen-3-yl group.
 9. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein Rhu 1 represents a2-chlorothiophen-3-yl group.
 10. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a2-methylpyridin-3-yl group.
 11. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a4-methylpyridin-3-yl group.
 12. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a2-ethylthio-pyridin-3-yl group.
 13. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a3,5-dimethylisoxazol-4-yl group.
 14. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a1,3-benzodioxol-4-yl group.
 15. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents a quinolin-4-ylgroup.
 16. A1-acyl-7-halo-2,3-dihydro-4(lH)-quinolinone-4-oxime-O-sulfonic acidcompound as claimed in claim 1 wherein R¹ represents aN-methylindol-2-yl group.
 17. A pharmaceutical composition comprising apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a1-acyl-7-halo-2,3-dihydro-4(lH)quinolinone-4-oxime-O-sulfonic acidcompound represented by the formula (I): ##STR81## wherein R¹ representsa phenyl group which should be substituted with at least one of analkylthio group, an amino group which may be substituted with one or twoalkyl groups of straight or branched chain having 1 to 4 carbon atoms, acarboxyl group, an aklyloxycarbonyl group of straight or branched chainhaving 1 to 4 carbon atoms or a phenyl group, or represnts a furylgroup, an isoxazolyl group, a pyrrolyl group, a pyridazinyl group, apyrimidinyl group, a quinolyl gorup, a benzodioxolyl group, a thienylgroup, a pyridyl group, an indolyl group or an indenyl group any one ofwhich may be substituted with at least one of an alkyl group of straightor branched chain having 1 to 4 carbon atoms, an alkylthio group, ahalogen atom, an amino group which may be substituted with one or twoalkyl groups of straight or branched chain having 1 to 4 carbon atoms, acarboxyl group, an alkyloxycarbonyl group of straight or branched chainhaving 1 to 4 carbon atoms or a phenyl group, provided that when R¹represents a thienyl group or a pyridyl group, either group should besubstituted with at least one of said substituents, X represents ahalogen atom, and the bond shown with a wavy line represents a bond ofanti-form or syn-form, and a salt thereof as well as a solvate of saidcompound and a solvate of said salt.
 18. A pharmaceutical composition asclaimed in claim 17 wherein R¹ represents a N-methylpyrrol-2-yl group.19. A pharmaceutical composition as claimed in claim 17 wherein R¹represents a furyl group.
 20. A pharmaceutical composition as claimed inclaim 17 wherein R¹ represents a 2,4-dimethylfuran-3-yl group.
 21. Apharmaceutical composition as claimed in claim 17 wherein R¹ representsa 2-methylthiophen-3-yl group.
 22. A pharmaceutical composition asclaimed in claim 17 wherein R¹ represents a 3-methylthiophen-2-yl group.23. A pharmaceutical composition as claimed in claim 17 wherein R¹represents a 4-methylthiophen-3-yl group.
 24. A pharmaceuticalcomposition as claimed in claim 17 wherein R¹ represents a2-ethylthiophen-3-yl group.
 25. A pharmaceutical composition as claimedin claim 17 wherein R¹ represents a 2-chlorothiophen-3-yl group.
 26. Apharmaceutical composition as claimed in claim 17 wherein R¹ representsa 2-methylpyridin-3-yl group.
 27. A pharmaceutical composition asclaimed in claim 17 wherein R¹ represents a 4-methylpyridin-3-yl group.28. A pharmaceutical composition as claimed in claim 17 wherein R¹represents a 2-ethylthio-pyridin-3-yl group.
 29. A pharmaceuticalcomposition as claimed in claim 17 wherein R¹ represents a3,5-dimethylisoxazol-4-yl group.
 30. A pharmaceutical composition asclaimed in claim 17 wherein R¹ represents a 1,3-benzodioxol-4-yl group.31. A pharmaceutical composition as claimed in claim 17 wherein R¹represents a quinolin-4-yl group.
 32. A pharmaceutical composition asclaimed in claim 17 wherein R¹ represents a N-methylindol-2-yl group.